Patent GB-923854-A (GB)
Title: New indene compounds and pharmaceutical preparation containing them
IPC: C07D213/38
Filed: 1959-08-12
Abstract: The invention comprises: indenes substituted in the 2-position by a tertiary amino-lower alkyl group (in which the tertiary amino group is a di-(C1-C5 alkyl)-amino group or an N,N-alkyleneimino group having 5 or 6 ring members, whose alkylene chain chain may be interrupted by nitrogen, oxygen or p  sulphur and which may be substituted by methyl groups, and the lower alkylene linking group contains 1-5 carbon atoms of which preferably 2 or 3 are in a straight chain between the nucleus and the N atom), substituted in the 3-position by a pyridyl-lower alkyl group (in which the pyridine ring is preferably unsubstituted but may be halogen- or C1-C5 alkyl- or alkoxy-substituted, and the alkylene linking group contains 1-3 carbon atoms), unsubstituted or C1-C5 alkyl - substituted in the 1 - position, and unsubstituted or halogen or C1-C5 alkyl- or alkoxy-substituted in the benzene ring), and their acid addition salts, quaternary ammonium compounds and N-oxides (in which the oxygen atom is attached to the nitrogen atom of the tertiary amino group); the preparation thereof by the following processes: (1) dehydrating a correspondingly substituted indan-1-, -2- or -3-ol, or one containing, instead of a tertiary amino group, a substituent subsequently converted thereto or replaced thereby, (2) shifting the double bond, by the action of an acid or base and/or by heating, in a correspondingly substituted D 2-indene, or one containing, instead of a tertiary amino group, a substituent subsequently converted thereto or replaced thereby, or (3) reducing (with shifting of the D 2-double bond) a 1-(pyridyl-lower alkylidene)-D 2-indene substituted in the 2-position in the same way as the starting materials in (1) and (2), and in all cases, if desired, converting a resulting acid addition salt into a free base by the action of alkali, or converting a resulting free base into an addition salt by reaction with an acid, into a quaternary ammonium salt by the action of an ester of an alkanol with a strong inorganic or organic acid, or into an N-oxide by the action of hydrogen peroxide in alcoholic solution; and pharmaceutical preparations containing the products in admixture or conjunction with a pharmaceutically suitable diluent. 1-Pyridyl-lower alkyl-2-tertiary amino-lower alkyl-indan-1-ols are prepared by reacting 2-tertiary amino-lower alkyl-indan-1-ones with pyridyl-lower alkyl metal compounds of groups Ia, IIa or IIb of the periodic system, especially lithium compounds, or with alkali metal salts of alkali metal pyridine lower alkanoic acids.  2-Tertiary amino-lower alkyl-indan-1-ones are prepared by reacting an a -benzylmalonic ester with a reactive ester of a tertiary amino-lower alkanol, preferably in the presence of an alkali metal alcoholate, and cyclizing the resulting ester, e.g. by hydrolysing and decarboxylating it, and heating the resulting substituted acetic acid with a Lewis acid.  a -Benzylmalonic esters are prepared by reacting benzyl halides with sodiomalonic esters.  Pyridyl-lower alkyl lithium compounds are prepared by reacting a lower alkyl-pyridine with an aryl or alkyl lithium, or reacting an ether of a pyridyl-lower alkanol and a lower alkanol with lithium.  1-Pyridyl-lower alkyl-2-tertiary amino-lower alkyl-indan-2-ols are prepared by reacting 1-pyridyl-lower alkylindan-2-ones with etherified hydroxy-lower alkyl Grignard reagents and then replacing the etherified hydroxy group by a tertiary amino group.  1-Pyridyl-lower alkyl-indan-2-ones are prepared by condensing indan-2-ones with pyridyl-lower alkyl-aldehydes in the presence of a base and reducing the resulting alkylidene compounds.  1-Pyridyl-lower alkyl-2-tertiary amino-lower alkyl-indan-3-ones are prepared by reacting 2-lower alkoxy-lower alkyl-3-lower alkoxy-inden-1-ones with pyridyl-lower alkyl metal compounds, dehydrating the products, hydrogenating the resulting double bond, converting the enol ether group to a 3-oxo group and reducing this, and finally replacing the lower alkoxy group by a tertiary amino group.  2-Lower alkoxy-lower alkyl-3-lower alkoxyinden-1-ones are prepared by reacting a lower alkyl phthalate with a lower alkoxy-lower alkyl-nitrile in the presence of a base and converting the resulting lower alkoxy-lower alkyl-indane-1,3-dione to its enol ether by treatment with an alcohol in the presence of an acid, or with a diazoalkane.  1-Pyridyl-lower alkyl-2-tertiary amino lower alkyl-D 2-indenes are prepared by reacting a 1-methyl-2-tertiary amino-lower alkyl-indene with a pyridine-lower alkyl-aldehyde in the presence of a base and reducing the resulting alkylidene compound.  1-(Pyridyl-lower alkylidene)-2-tertiary amino-lower alkyl D 2-indenes are prepared by condensing a 2-tertiary amino-lower alkyl-indene with a pyridyl-lower alkanol or with a lower alkenyl-pyridine.  Di-tetrahydropyranyl a -benzylmalonate is prepared by reacting a -benzylmalonic acid with dihydropyran in ether in the presence of p-toluenesulphonic acid.  2-(2- Dimethylaminoethyl)- indene hydrochloride is prepared by reducing 2-(2-dimeth aminoethyl)-indan-1-one with sodium borohydride and refluxing the resulting 2-(2-dimethylaminoethyl)-indan-1-ol (the picrate of which is described) with concentrated hydrochloric acid and glacial acetic acid.  2-(3-Dimethylaminoethyl)-indene hydrochloride is prepared analogously.  The pharmaceutical preparations, which have antihistaminic, sedative, tranquillizing and local anaesthetic action, may be in forms suitable for enteral, parenteral or topical administration, e.g. tablets, dragees, salves, creams, solutions, suspensions or emulsions.